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WO2023226900A1 - Dérivé de 2-(pipérazine-2-yl)acétonitrile, son procédé de préparation et son utilisation - Google Patents

Dérivé de 2-(pipérazine-2-yl)acétonitrile, son procédé de préparation et son utilisation Download PDF

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Publication number
WO2023226900A1
WO2023226900A1 PCT/CN2023/095358 CN2023095358W WO2023226900A1 WO 2023226900 A1 WO2023226900 A1 WO 2023226900A1 CN 2023095358 W CN2023095358 W CN 2023095358W WO 2023226900 A1 WO2023226900 A1 WO 2023226900A1
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Prior art keywords
compound
acid
acetonitrile
inert solvent
piperazin
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Chinese (zh)
Inventor
吕彬华
冯卫东
崔大为
廉昌明
刘连军
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Suzhou Zelgen Biopharmaceutical Co Ltd
Shanghai Zelgen Pharmatech Co Ltd
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Suzhou Zelgen Biopharmaceutical Co Ltd
Shanghai Zelgen Pharmatech Co Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B59/00—Introduction of isotopes of elements into organic compounds ; Labelled organic compounds per se
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
    • C07C51/41—Preparation of salts of carboxylic acids
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C59/00—Compounds having carboxyl groups bound to acyclic carbon atoms and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
    • C07C59/235—Saturated compounds containing more than one carboxyl group
    • C07C59/245—Saturated compounds containing more than one carboxyl group containing hydroxy or O-metal groups
    • C07C59/255—Tartaric acid
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
    • C07D241/02—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings
    • C07D241/04—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Definitions

  • the invention belongs to the technical field of drug synthesis, and specifically relates to a preparation method and application of 2-(piperazin-2-yl)acetonitrile or its salt and its derivatives.
  • Lung cancer is one of the important causes of cancer death in humans.
  • Lung cancer can be divided into small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC) according to cell type, with NSCLC accounting for 85% of all lung cancer patients.
  • SCLC small cell lung cancer
  • NSCLC non-small cell lung cancer
  • the global NSCLC market in 2016 was approximately US$20.9 billion, of which the US market accounted for half, followed by Japan, Germany and China.
  • the non-small cell lung cancer market has maintained continued growth, and the global market is expected to reach US$54 billion in 2023 (Nature, 2018; 553(7689):446-454).
  • KRAS mutations are frequently detected in lung cancer patients and account for approximately 32% of all oncogene mutations.
  • KRAS G12C mutation accounts for 44% of all oncogene mutations in NSCLC. Since the KRAS G12C target protein is pathologically associated with a variety of diseases, novel KRAS G12C inhibitors are currently needed for clinical treatment. Highly selective and active KRAS G12C inhibitors can more effectively treat diseases such as cancer caused by KRAS G12C mutations, as well as have the potential to reduce off-target effects, so they have a more urgent clinical need.
  • KRASG12C inhibitors currently in clinical stages include AMG510, MRTX849, ARS-3248 and LY-3499446, among which MRTX849 has demonstrated good efficacy and safety in phase I clinical trials.
  • MRTX849 uses the S-2-(piperazin-2-yl)acetonitrile structure to increase the binding of KRAS G12C protein, improve the pharmacokinetic properties and increase the inhibitory effect of KRAS G12C protein (J Med Chem. 2020 Apr 6.doi :10.1021/acs.jmedchem.9b02052.).
  • 2-(piperazin-2-yl)acetonitrile is also widely used as an important pharmacophore group in PKC inhibitors (WO/2014/052699) and antibiotics (Journal of Heterocyclic Chemistry, 1992, 29(1), 55- 59) and other drug molecular structures.
  • deuteration strategies are often used in drug synthesis.
  • the metabolic site is blocked, the clearance rate in the organism is slowed down, and the half-life is extended, thereby improving the pharmacokinetic properties while reducing the generation of toxic metabolites.
  • Patents WO2014052699, WO2017201161, etc. report the preparation method of racemic 2-(piperazin-2-yl)acetonitrile derivatives.
  • the synthesis method is as shown in Route 1.
  • Route 1 uses allyl nitrile as the starting material, which is added with bromine to form A17 or added with bromine and then eliminated to form A07, which is then reacted with N1, N2-diphenylmethylethane-1,2- Diamine ring closure reaction gives A18, and debenzylation gives A19.
  • This route can obtain racemic A19, but the existing synthesis method has low yield and requires at least two column chromatography purifications, so it is not suitable for industrial production.
  • Patent WO2017201161, US20180072723, etc. report the preparation method of chiral (S)-2-(piperazin-2-yl)acetonitrile derivatives.
  • the synthesis method is as shown in Route 2.
  • Route 2 uses B01 containing a chiral center as the starting material, first activates the hydroxyl group of B01, then replaces the activated hydroxyl group with a cyano group to introduce a cyano group, and finally removes protection to obtain A22.
  • This synthesis route has the disadvantages of expensive starting material B01, highly toxic reagents used in the reaction, and multiple column chromatography purifications, so it is not suitable for industrial production.
  • the purpose of the present invention is to provide a synthesis method of 2-(piperazin-2-yl)acetonitrile or its salt and its derivatives.
  • This compound is an intermediate of a KRAS G12C inhibitor,
  • This synthesis method has low cost, safe and environmentally friendly process, and column-free chromatography operation, which is more suitable for industrial production.
  • the purpose of the present invention is to provide a synthesis method of 2-(piperazin-2-yl)acetonitrile or its salt and its derivatives.
  • This compound is an intermediate of a KRAS G12C inhibitor,
  • This synthesis method has low cost, safe and environmentally friendly process, and column-free chromatography operation, which is more suitable for industrial production.
  • a first aspect of the present invention provides a method for preparing compound A22 or a salt thereof, the method comprising:
  • compound A20 reacts with an amino protecting agent to obtain compound A21;
  • compound A21 is deprotected to obtain compound A22 or a salt thereof;
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 and R 11 are each independently H or D;
  • X 1 , X 2 , X 3 and X 4 are each independently none, organic acid or inorganic acid;
  • P 1 and P 2 are each independently an amino protecting group
  • 0 ⁇ n ⁇ 10 preferably, 0 ⁇ n ⁇ 8, more preferably, 0.5 ⁇ n ⁇ 5.
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 and R 11 are all H.
  • R 1 and R 2 are D, and R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 and R 11 are all H.
  • R 6 , R 7 , R 8 and R 9 are D, and R 1 , R 2 , R 3 , R 4 , R 5 , R 10 and R 11 are H.
  • R 1 , R 2 , R 6 , R 7 , R 8 and R 9 are D, and R 3 , R 4 , R 5 , R 10 and R 11 are H.
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 and R 9 are D, and R 10 and R 11 are H.
  • R 3 , R 4 , R 5 , R 6 , R 7 , R 8 and R 9 are D, and R 1 , R 2 , R 10 and R 11 are H.
  • R 3 , R 4 , and R 5 are D, and R 1 , R 2 , R 6 , R 7 , R 8 , R 9 , R 10 and R 11 are H.
  • R 1 , R 2 , R 3 , R 4 and R 5 are D, and R 6 , R 7 , R 8 , R 9 , R 10 and R 11 are H.
  • R 1 , R 2 , R 4 , R 5 , R 6 , R 7 , R 8 and R 9 are D, and R 3 , R 10 and R 11 are H.
  • the amino protecting agent is selected from: di-tert-butyl dicarbonate, benzyl chloroformate, benzyl bromoformate, benzyl chloride, benzyl bromide, triphenyl chloride, triphenyl bromide, chlorine 9-fluorenylmethyl formate, 9-fluorenylmethyl bromoformate, allyl chloroformate, allyl bromoformate, 2,2,2-trifluoroacetyl chloride, benzenesulfonyl chloride, p-toluenesulfonyl chloride , Acetyl chloride, pivaloyl chloride, 1-(chloromethyl)-4-methoxybenzene, 1-(bromomethyl)-4-methoxybenzene, 1-(chloromethyl)-2,4- Dimethoxybenzene, 1-(bromomethyl)-2,4-dimethoxybenzene, o-(p-)nitro
  • n is 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2.0, 2.1, 2.2, 2.3, 2.4, 2.5 ,2.6,2.7,2.8,2.9,3.0,3.1,3.2,3.3,3.4,3.5,3.6,3.7,3.8,3.9,4.0,4.1,4.2,4.3,4.4,4.5,4.6,4.7,4.8,4.9,5.0 .
  • P 1 and P 2 are each independently tert-butoxycarbonyl, benzyloxycarbonyl, benzyl, trityl, fluorenylmethoxycarbonyl, allyloxycarbonyl, trifluoroacetyl, benzene sulfonyl Acyl, p-toluenesulfonyl, acetyl, pivaloyl, 4-methoxybenzyl, 2,4-dimethoxybenzyl, o-(p-)nitrobenzenesulfonyl.
  • compound A22 is compound A'22, and its preparation method includes:
  • the molar equivalent ratio of the chiral acid to compound A19 is 0.1 to 10 equivalents; preferably, it is 0.5 to 5 equivalents.
  • step s1) when compound A19 is a salt, the solution of the salt of compound A19 is first adjusted to neutral or alkaline with a base, then a chiral acid is added, and finally compound A20 is precipitated (i.e., (S)-2-(Piperazin-2-yl)acetonitrile diastereomeric salt with chiral acid).
  • the base is selected from: sodium bicarbonate, sodium carbonate, potassium carbonate, cesium carbonate, potassium phosphate, sodium methoxide, sodium ethoxide, sodium tert-butoxide, potassium tert-butoxide, lithium hydroxide, hydrogen Sodium oxide, potassium hydroxide, lithium diisopropylamide (LDA), lithium hexamethyldisilazide (LiHMDS), triethylamine (TEA), N,N-diisopropylethylamine (DIPEA), 1,8-diazabicycloundec-7-ene (DBU), or a combination thereof; preferably, the base is selected from: sodium bicarbonate, sodium carbonate, potassium carbonate, cesium carbonate, potassium phosphate, methanol Sodium, sodium ethoxide, sodium tert-butoxide, potassium tert-butoxide, lithium hydroxide, sodium hydroxide, potassium hydroxide, or a combination thereof; more preferably,
  • step s1) when compound A19 is a salt, the solution of the salt of compound A19 is first adjusted to neutral or alkaline with a base, wherein the molar equivalent ratio of the base to compound A19 is 1.0 ⁇ 3.0:1, preferably 1.5 ⁇ 2.0:1, more preferably 1.5 ⁇ 1.8:1.
  • the reaction temperature is -50°C to solvent reflux temperature, preferably the reaction temperature is -30°C to 100°C, more preferably, the reaction temperature is -15°C to 50°C, more preferably, The reaction temperature is 20°C to 50°C, for example, 25 to 50°C.
  • compound A20 is (S)-2-(piperazin-2-yl)acetonitrile salt, which is selected from the D-tartrate salt of (S)-2-(piperazin-2-yl)acetonitrile. , D-malic acid of (S)-2-(piperazin-2-yl)acetonitrile, R-(-)-citramalic acid of (S)-2-(piperazin-2-yl)acetonitrile, or its combination.
  • the chiral acid is selected from: L-tartaric acid, D-tartaric acid, dibenzoyl-L-tartaric acid, dibenzoyl-D-tartaric acid, di-p-toluoyl-L-tartaric acid, Di-p-toluoyl-D-tartaric acid, L-dipivaloyl tartaric acid, L-malic acid, D-malic acid, R-(-)-citramalic acid, S-(+)-citramalic acid, R-( -)-mandelic acid, S-(+)-mandelic acid, D-(+)-10-camphorsulfonic acid, L-(-)-10-camphorsulfonic acid, D-camphoric acid, or combinations thereof; preferably , the chiral acid is selected from: D-tartaric acid, D-malic acid, dibenzoyl-D-tartaric acid, R-(-)-citramalic acid, R
  • the molar equivalent ratio of compound A20 to the amino protecting agent is 1.0:0.1-10 equivalents, preferably 1.0:0.5-5.0, more preferably 1.0:1.0-3.0.
  • the reaction temperature is -50°C to the solvent reflux temperature, preferably the reaction temperature is -30°C ⁇ 100°C, more preferably, the reaction temperature is -5°C ⁇ 50°C, more preferably Preferably, the reaction temperature is 20 to 25°C.
  • the reaction temperature is -20°C to the solvent reflux temperature, preferably the reaction temperature is -10°C ⁇ 100°C, more preferably, the reaction temperature is 0°C ⁇ 60°C, more preferably Ground, the reaction temperature is 20 ⁇ 25°C.
  • step s3) compound A21 is deprotected under acidic conditions to obtain compound A22, wherein the acid is selected from: hydrogen chloride, hydrogen bromide, hydrogen fluoride, phosphoric acid, sulfuric acid, acetic acid, Trifluoroacetic acid, methanesulfonic acid, p-toluenesulfonic acid, benzenesulfonic acid, camphorsulfonic acid, oxalic acid, malic acid, citric acid, or combinations thereof; the molar equivalent ratio of compound A21 to acid is 1.0:0.1-20 equivalents, preferably 1.0:0.5 ⁇ 10.0, more preferably 1.0:1.0 ⁇ 5.0.
  • the acid is selected from: hydrogen chloride, hydrogen bromide, hydrogen fluoride, phosphoric acid, sulfuric acid, acetic acid, Trifluoroacetic acid, methanesulfonic acid, p-toluenesulfonic acid, benzenesulfonic acid, camphorsulfonic acid, o
  • the method further includes adding a base to obtain the free base of compound A22.
  • the purity of compound A20 or compound A22 is greater than 95%, preferably, greater than 97%, more preferably, greater than 98%.
  • the chiral purity of compound A20 or compound A22 is greater than 95%, preferably greater than 97%, more preferably greater than 99%.
  • A19 is 2-(piperazin-2-yl)acetonitrile or its hydrochloride, and its preparation method includes the steps:
  • compound A18 is removed from the protecting group in the presence of 1-chloroethyl chloroformate to obtain compound A’19;
  • compound A18 is removed from the protecting group in the presence of 1-chloroethyl chloroformate to obtain compound A’19.
  • A19 is 2-(piperazin-2-yl)acetonitrile-d 2 or its hydrochloride, 2-(piperazin-2-yl-5,5,6,6-d 4 ) Acetonitrile or its hydrochloride, 2-(piperazin-2-yl-2,3,3,5,5,6,6-d 7 )acetonitrile-d 2 or its hydrochloride, its preparation method includes the steps: :
  • compound A01 reacts with a deuterated reducing agent to obtain compound A02;
  • compound A02 reacts with a halogenated reagent to obtain compound A03;
  • compound A03 reacts with sodium cyanide or potassium cyanide to obtain compound A04;
  • compound A04 is removed from the protecting group in the presence of 1-chloroethyl chloroformate to obtain compound A05;
  • compound A06 reacts with a bromine reagent, and then an elimination reaction occurs under the action of a base to obtain compound A07;
  • compound A08 is removed from the protecting group in the presence of 1-chloroethyl chloroformate to obtain compound A09;
  • compound A11 reacts with N 1 , N 2 -dibenzylethane-d 4 -1,2-diamine to obtain compound A12;
  • compound A12 reacts with a deuterated reducing agent to obtain compound A13;
  • compound A13 reacts with a halogenated reagent to obtain compound A14;
  • compound A14 reacts with sodium cyanide or potassium cyanide to obtain compound A15;
  • the deuterated reducing agent is lithium deuterated aluminum tetrahydrogen.
  • the halogenating reagent is sulfoxide chloride, phosphorus trichloride, phosphorus pentachloride, phosphorus oxychloride, oxalyl chloride, or a combination thereof.
  • the inert solvent is selected from: ethyl acetate, isopropyl acetate, dichloromethane, 1,2-dichloroethane, chloroform, carbon tetrachloride, tetrahydrofuran, dimethyl Tetrahydrofuran, methyl tert-butyl ether, petroleum ether, n-heptane, n-hexane, pentane, cyclohexane, N,N-dimethylformamide (DMF), N,N-dimethylacetamide (DMA) ), dimethyl sulfoxide (DMSO), N-methylpyrrolidone (NMP), ethylene glycol dimethyl ether (DME), acetonitrile, acetone, benzene, toluene, chlorobenzene, methanol, ethanol, tert-butanol, isopropyl Alcohol, n-propanol, n-butyl ether, petroleum ether
  • the bromine reagent is selected from: bromine or tribromopyridinium salt.
  • step (i') also includes distillation under reduced pressure to obtain purified compound A07.
  • step (ii) or (ii') also includes recrystallizing compound A18 using a crystallization solvent to obtain purified compound A18, wherein the crystallization solvent is selected from: methanol, ethanol, petroleum ether, n-heptane, cyclohexane, n-hexane, methylcyclohexane, pentane, or combinations thereof.
  • the crystallization solvent is selected from: methanol, ethanol, petroleum ether, n-heptane, cyclohexane, n-hexane, methylcyclohexane, pentane, or combinations thereof.
  • the base is selected from: sodium methoxide, sodium ethoxide, sodium tert-butoxide, tert-butyl Potassium alkoxide, sodium tert-amyloxide, 1,4-diazabicyclo[2.2.2]octane (DABCO), 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) , 1,5-diazabicyclo[4.3.0]undec-7-ene (DBN), lithium diisopropylamide (LDA), lithium 2,2,6,6-tetramethylpiperidine, Lithium hexamethyldisilazide (LHMDS), potassium hexamethyldisilamide (KHMDS), or a combination thereof; preferably, the base is selected from: sodium methoxide, sodium ethoxide, sodium tert-butoxide, tert.
  • the base is selected from: sodium methoxide, sodium ethoxide, sodium tert-butoxide, potassium tert-butoxide, sodium tert-amyloxide, or combinations thereof.
  • the inert solvent is selected from: dichloromethane, 1,2-dichloroethane, chloroform, carbon tetrachloride, ethyl acetate, isopropyl acetate Esters, tetrahydrofuran, 2-methyltetrahydrofuran, methyl tert-butyl ether, dioxane, acetone, acetonitrile, petroleum ether, n-heptane, n-hexane, pentane, cyclohexane, N,N-dimethyl Formamide (DMF), N,N-dimethylacetamide (DMA), dimethyl sulfoxide (DMSO), N-methylpyrrolidone (NMP), ethylene glycol dimethyl ether (DME), benzene, toluene, Chlorobenzene, or a combination thereof; preferably, the inert solvent is selected from: to
  • the base in step (ii) or (ii'), is selected from: sodium carbonate, potassium carbonate, cesium carbonate, sodium methoxide, sodium ethoxide, sodium tert-butoxide, potassium tert-butoxide, triethylamine , 1-methylpyrrolidine, 1-methylpiperidine, dimethylisopropylamine, N,N-diisopropylethylamine, N-methylmorpholine, imidazole, pyridine, 2-methylpyridine, 2 ,6-dimethylpyridine, 4-dimethylaminopyridine (DMAP), 1,4-diazabicyclo[2.2.2]octane (DABCO), 1,8-diazabicyclo[5.4.0] Undec-7-ene (DBU), 1,5-diazabicyclo[4.3.0]undec-7-ene (DBN), or a combination thereof; preferably, the base is selected from: sodium carbonate , potassium carbonate, sodium meth
  • the inert solvent is selected from: dichloromethane, 1,2-dichloroethane, chloroform, carbon tetrachloride, ethyl acetate, isopropyl acetate Esters, tetrahydrofuran, 2-methyltetrahydrofuran, methyl tert-butyl ether, dioxane, acetone, acetonitrile, petroleum ether, n-heptane, n-hexane, pentane, cyclohexane, N,N-dimethyl Formamide (DMF), N,N-dimethylacetamide (DMA), dimethyl sulfoxide (DMSO), N-methylpyrrolidone (NMP), ethylene glycol dimethyl ether (DME), benzene, toluene, Chlorobenzene, or a combination thereof; preferably, the inert solvent is selected from: dichloromethane, 1,2-dichloroethane, chlor
  • reaction temperature is 25-120°C, preferably 50-110°C, and more preferably 70-100°C.
  • step (iii) or (iii') further includes adding a base to obtain the free base of compound A19.
  • the present invention provides a method for preparing compound A20, which method includes the steps:
  • X 1 and X 2 are each independently free, organic acid or inorganic acid
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 and R 11 are each independently H or D;
  • n 0 ⁇ n ⁇ 10, preferably, 0 ⁇ n ⁇ 8, more preferably, n is 0.5 ⁇ n ⁇ 5.
  • compound A20 is a diastereomeric salt of (S)-2-(piperazin-2-yl)acetonitrile and chiral acid, and its preparation method includes the steps
  • n 0 ⁇ n ⁇ 10, preferably, 0 ⁇ n ⁇ 8, more preferably, n is 0.5 ⁇ n ⁇ 5;
  • the molar equivalent ratio of the chiral acid to compound A19 is 0.1 to 10 equivalents; preferably, the molar equivalent ratio is 0.5 to 5 equivalents.
  • the base is selected from: sodium bicarbonate, sodium carbonate, potassium carbonate, cesium carbonate, potassium phosphate, sodium methoxide, sodium ethoxide, sodium tert-butoxide, potassium tert-butoxide, lithium hydroxide, hydrogen Sodium oxide, potassium hydroxide, lithium diisopropylamide (LDA), lithium hexamethyldisilazide (LiHMDS), triethylamine (TEA), N,N-diisopropylethylamine (DIPEA), 1,8-diazabicycloundec-7-ene (DBU), or a combination thereof; preferably, the base is selected from: sodium bicarbonate, sodium carbonate, potassium carbonate, cesium carbonate, potassium phosphate, methanol Sodium, sodium ethoxide, sodium tert-butoxide, potassium tert-butoxide, lithium hydroxide, sodium hydroxide, potassium hydroxide, or a combination thereof; more preferably,
  • the molar equivalent ratio of the base to compound A'19 is 1.0-3.0:1, preferably 1.5-2.0:1, more preferably 1.5-1.8:1.
  • the reaction temperature is -50°C to the solvent reflux temperature, and the preferred reaction temperature is -30°C. to 100°C, more preferably, the reaction temperature is -15°C to 50°C, more preferably, the reaction temperature is 20°C to 50°C, such as 25 to 50°C.
  • compound A'20 is selected from the group consisting of D-tartrate salt of (S)-2-(piperazin-2-yl)acetonitrile, (S)-2-(piperazin-2-yl)acetonitrile.
  • the present invention provides a compound A20, which is prepared by the method described in the second aspect.
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 and R 11 are each independently H or D;
  • n 0 ⁇ n ⁇ 10, preferably, 0 ⁇ n ⁇ 8, more preferably, n is 0.5 ⁇ n ⁇ 5.
  • the fourth aspect of the present invention provides a compound represented by formula I or a salt, enantiomer, diastereomer, or racemate thereof,
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 and R 11 are each independently H or D; the limiting condition is R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 and R 11 are not hydrogen at the same time.
  • the compound of formula I has the structure shown in formula I'
  • * indicates R or S configuration
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 and R 11 are defined as above.
  • the compound is selected from:
  • the compound is selected from:
  • inert solvent refers to a reagent that does not react with the reaction substrate.
  • Intermediates refer to semi-finished products, which are products formed during the production of the required products. Typically, inventors can proceed to the production of products from intermediates as starting materials. Therefore, screening suitable intermediates can optimize the process route, thereby increasing the yield and saving time and cost.
  • the intermediate of the present invention is selected from compound A20
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 and R 11 are each independently H or D; the qualification is R 1 , R 2 , R 3. R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 and R 11 are not hydrogen at the same time;
  • n 0 ⁇ n ⁇ 10, preferably, 0 ⁇ n ⁇ 8, more preferably, 0.5 ⁇ n ⁇ 5, for example, n is 1-3.
  • the chiral acid is D-tartaric acid.
  • the intermediate of the present invention is And A'20 is prepared by the following method
  • 0 ⁇ n ⁇ 10 preferably, 0 ⁇ n ⁇ 8, more preferably, 0.5 ⁇ n ⁇ 5, for example, n is 1-3, and the chiral acid is D-tartaric acid.
  • the intermediate of the present invention is selected from compounds represented by formula (I) or salts thereof,
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 and R 11 are each independently H or D; the limiting condition is R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 and R 11 are not hydrogen at the same time.
  • the salt of the compound of formula (I) may be an HCl salt.
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 and R 11 can all be H.
  • R 1 and R 2 are D, and R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 and R 11 are all H.
  • R 6 , R 7 , R 8 and R 9 are D, and R 1 , R 2 , R 3 , R 4 , R 5 , R 10 and R 11 are H.
  • R 1 , R 2 , R 6 , R 7 , R 8 and R 9 are D, and R 3 , R 4 , R 5 , R 10 and R 11 are H.
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 and R 9 are D, and R 10 and R 11 are H.
  • R 3 , R 4 , R 5 , R 6 , R 7 , R 8 and R 9 are D, and R 1 , R 2 , R 10 and R 11 are H.
  • R 3 , R 4 , and R 5 are D, and R 1 , R 2 , R 6 , R 7 , R 8 , R 9 , R 10 and R 11 are H.
  • R 1 , R 2 , R 3 , R 4 and R 5 are D, and R 6 , R 7 , R 8 , R 9 , R 10 and R 11 are H.
  • R 1 , R 2 , R 4 , R 5 , R 6 , R 7 , R 8 and R 9 are D, and R 3 , R 10 and R 11 are H.
  • the preparation method of compound A20 includes
  • X 1 and X 2 are each independently inorganic, organic or inorganic acid
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 and R 11 are each independently H or D;
  • n 0 ⁇ n ⁇ 10, preferably, 0 ⁇ n ⁇ 8, more preferably, n is 0.5 ⁇ n ⁇ 5.
  • the preparation method includes
  • compound A’19 reacts with a chiral acid to obtain compound A’20;
  • n 0 ⁇ n ⁇ 10, preferably, 0 ⁇ n ⁇ 8, more preferably, n is 0.5 ⁇ n ⁇ 5.
  • the method further includes
  • (2')3-Bromoacrylonitrile reacts with N 1 , N 2 -diphenylmethylethane-1,2-diamine ring closure to obtain 2-(1,4-diphenylmethylpiperazine-2- base) acetonitrile; in this step, purified 2-(1,4-diphenylmethylpiperazin-2-yl)acetonitrile can be obtained by recrystallization; the crystallization solvent is selected from methanol, ethanol, petroleum ether, n-heptane , cyclohexane, n-hexane, methylcyclohexane, pentane, or combinations thereof;
  • the method also includes
  • Methyl 1,4-dibenzylpiperazine-2-carboxylate reacts with lithium deuterated tetrahydrogen aluminum to obtain (1,4-dibenzylpiperazine-2-yl)methane-d 2 -Alcohol;
  • But-3-enenitrile undergoes an addition reaction before bromine or tribromopyridinium salt, and then undergoes an elimination reaction under the action of a base to obtain 4-bromobut-2-enenitrile;
  • the ratio of each reaction material is not particularly limited, and the molar ratio of the reactants can be 5.0-0.5:1 (such as 2:1, 3:1, 1.5:1 or 1:1, etc.).
  • the base in each step, can be an organic base, an inorganic base, or a combination thereof, such as: sodium bicarbonate, sodium carbonate, potassium carbonate, cesium carbonate, potassium phosphate, sodium methoxide, sodium ethoxide, sodium tert-butoxide , Potassium tert-butoxide, lithium hydroxide, sodium hydroxide, potassium hydroxide, lithium diisopropylamide (LDA), lithium hexamethyldisilazide (LiHMDS), triethylamine (TEA), N,N -Diisopropylethylamine (DIPEA), 1,8-diazabicycloundec-7-ene (DBU), or combinations thereof, the molar ratio of base and reactant is 1.0-8.0:1, such as 2.01:1, 3:1, 1.5:1 or 1:1 etc.
  • LDA lithium diisopropylamide
  • LiHMDS lithium hexamethyldisilazide
  • TAA triethy
  • the reaction solvent, reaction temperature, reaction time, etc. can be selected according to the specific reactants.
  • the reaction solvent can be: ethyl acetate, isopropyl acetate, dichloromethane, 1,2-dichloromethane, etc.
  • the present invention provides a novel and efficient synthesis of 2-(piperazin-2-yl)acetonitrile or its salts and derivatives thereof;
  • the starting raw materials used in the process of the present invention are cheap and easy to obtain;
  • the process of the present invention avoids the use of highly toxic reagents to introduce cyano groups
  • the process of the present invention avoids the use of multiple column chromatography purification operations
  • the process of the present invention is simple to operate and easy to purify, and can obtain high-quality, high-purity intermediates and 2-(piperazin-2-yl)acetonitrile or its salts and derivatives thereof;
  • the present invention can prepare 2-(piperazin-2-yl)acetonitrile or its salts and derivatives thereof with high chiral purity;
  • the new route of the present invention has greater advantages and stronger industrialization prospects than the existing methods.
  • N 1 , N 2 -diphenylmethylethane-1,2-diamine 53g, 0.22mol, 1.0eq
  • triethylamine 50g, 0.48mol, 2.2eq
  • toluene 100mL
  • slowly add the previously reserved reaction solution adjust the temperature to 45-50°C, stir for 1 hour, and solid will precipitate.
  • Filter distill the filtrate under reduced pressure to remove the solvent, add methanol (30 mL), adjust the temperature to 0-5°C and stir for 2 hours to precipitate a solid. Filter, take out the filter cake, and dry to obtain 47 g of the title compound, with a purity of 97% and a yield of 70%.
  • N 1 , N 2 -diphenylmethylethane-1,2-diamine (196g, 0.82mol, 1.0eq) and triethylamine (165g, 1.63mol, 2.0eq) in sequence.
  • toluene 500mL was added to a three-necked flask, and a toluene solution of 3-bromoacrylonitrile (119g, 0.82mol, 1.0eq, 200mL of toluene) was added. After stirring for 16 hours, a solid precipitated.
  • Filter remove the solvent from the filtrate under reduced pressure, add methanol (200 mL) to the concentrate, and stir for 1 hour at 0 to 5°C to precipitate a white solid. Filter, take out the filter cake, and dry to obtain 200 g of the title compound, with a purity of 97% and a yield of 80%.
  • N 1 , N 2 -dibenzyl ethane-d 4 -1,2-diamine is substituted for N 1 , N 2 -dibenzyl ethane-1,2-diamine to obtain the following Compounds:
  • Step 1 (1,4-Dibenzylpiperazin-2-yl)methane-d 2 -ol
  • 1,4-dibenzylpiperazine-2-carboxylic acid methyl ester (3.00g, 9.25mmol) was added in batches to a suspension of deuterated aluminum lithium hydride (1.7g, 40.6mmol) in tetrahydrofuran at room temperature.
  • the obtained reaction solution was refluxed for 3 hours, then cooled to 0°C, and then water (1.5 mL), 4N NaOH aqueous solution (1.5 mL) and water (4.5 mL) were added in sequence.
  • the obtained mixture was stirred for 1 hr and then filtered, and the filtrate was concentrated under reduced pressure to obtain the target product (2.76 g, quantitative yield). It was used directly in the next reaction without purification.
  • Methyl 2,3-dibromopropionate-2,3,3-d 3 (2.5g, 10mmol) and Et 3 N (2.9mL) obtained in the previous step were dissolved in toluene (20mL), and then heated to 50°C , then N 1 , N 2 -dibenzylethane-d 4 -1,2-diamine (2.44g, 10mmol) was added dropwise.
  • the reaction solution was refluxed overnight and then cooled to room temperature, and then extracted with 2N HCl aqueous solution. After the aqueous phase was separated, it was neutralized with 4N NaOH aqueous solution and extracted with EtOAc.
  • Steps 3 to 6 Synthesize the following compounds according to the same method as Example 7B:
  • 2-(piperazin-2-yl-2,3,3,5,5,6,6-d 7 )acetonitrile-d 2 hydrochloride 5g, 24mmol, 1.0eq
  • Dissolve in water (10 mL) dissolve clear, add sodium hydroxide aqueous solution (1.4g, 36mmol, 1.5eq, 20mL of water), stir for 10 minutes, then add D-tartaric acid (72g, 5mmol, 2.0eq) to the above solution medium, adjust the temperature to 80-85°C, slowly add ethanol (20 mL), and naturally cool to 20-25°C to precipitate a white solid. Filter, take out the filter cake, and obtain 6.4 g of the title compound after drying.

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Abstract

La présente invention concerne le 2-(pipérazine-2-yl)acétonitrile ou un sel de celui-ci, un dérivé de celui-ci et un procédé de synthèse de celui-ci. La voie de traitement du procédé selon la présente invention est simple et efficace, engendre des coûts et une pollution faible, offre une haute innocuité et n'implique pas de purification par chromatographie sur colonne. Le produit cible préparé présente une pureté HPLC supérieure à 98 % et une valeur ee supérieure à 99 %. Par conséquent, le procédé de préparation est plus approprié pour une application industrielle.
PCT/CN2023/095358 2022-05-27 2023-05-19 Dérivé de 2-(pipérazine-2-yl)acétonitrile, son procédé de préparation et son utilisation Ceased WO2023226900A1 (fr)

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